GROWTH-INHIBITION OF HUMAN KERATINOCYTES BY A NEW VITAMIN-D-3 ANALOG IN-VITRO

SM-10193 (26,26,26,27,27,27-hexafluoro-1 alpha,23(S),25-trihydroxyvita min D-3; F-6-1,23(S),25-(OH)D-3) is one of the active vitamin D-3 anal ogues, which is under exploration as a new therapeutic agent for psori asis. In this paper, we present that SM-10193 induces the growth inhib ition and differentiation of cultured normal human keratinocytes more effectively than 1,25(OH)(2)D-3. The growth of keratinocytes was inhib ited in the presence of 10(-11), 10(-10), 10(-9) 10(-8), 10(-7) and 10 (-6) M of SM-10193 by 36.8, 42.1, 48.5, 47.6, 66.0 and 85.9% respectiv ely, SM-10193 increased the number of involucrin positive cells (the m arker for keratinocyte differentiation) from 4.9+/-0.1 to 12.5+/-0.8, 20.1 +/- 1.6 and 42.8 +/- 1.0% (P < 0.01) at 10(-8), 10(-7) and 10(-6) M, respectively. To elucidate the mechanism of SM-10193-induced growt h inhibition, we analyzed cell cycle related distribution and the alte ration of hyperphosphorylated and hypophosphorylated stale of retinobl astoma protein (pRB). SM-10193 induces growth arrest in G1/G0 and G2 M phases and an increase of the hypophosphorylated form of pRB more r emarkably than 1,25(OH)(2)D-3 does. (C) 1998 Elsevier Science Ireland Ltd.